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Disparities within mothers' health-related seeking behavior pertaining to frequent childhood morbidities within Ethiopia: determined by nationally agent info.
Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.Objective To investigate the pattern of progression of neurologic impairment in Friedreich ataxia (FRDA) and identify patients with fast disease progression as detected by clinical rating scales. Methods Clinical, demographic, and genetic data were analyzed from 54 patients with FRDA included at the Brussels site of the European Friedreich's Ataxia Consortium for Translational Studies, with an average prospective follow-up of 4 years. Results Afferent ataxia predated other features of FRDA, followed by cerebellar ataxia and pyramidal weakness. The Scale for the Assessment and Rating of Ataxia (SARA) best detected progression in ambulatory patients and in the first 20 years of disease duration but did not effectively capture progression in advanced disease. Dysarthria, sitting, and upper limb coordination items kept worsening after loss of ambulation. Eighty percent of patients needing support to walk lost ambulation within 2 years. Age at onset had a strong influence on progression of neurologic and functional deficits, which was maximal in patients with symptom onset before age 8 years. All these patients became unable to walk by 15 years after onset, significantly earlier than patients with later onset. Progression in the previous 1 or 2 years was not predictive of progression in the subsequent year. Conclusions The SARA is a sensitive outcome measure in ambulatory patients with FRDA and has an excellent correlation with functional capabilities. Ivacaftor purchase Ambulatory patients with onset before age 8 years showed the fastest measurable worsening. Loss of ambulation in high-risk patients is a disease milestone that should be considered as an end point in clinical trials. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.Objective To investigate the effect of somatic, postzygotic, gain-of-function mutation of Endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1) encoding hypoxia-inducible factor-2α (HIF-2α) on posterior fossa development and spinal dysraphism in EPAS1 gain-of-function syndrome, which consists of multiple paragangliomas, somatostatinoma, and polycythemia. Methods Patients referred to our institution for evaluation of new, recurrent, and/or metastatic paragangliomas/pheochromocytoma were confirmed for EPAS1 gain-of-function syndrome by identification of the EPAS1 gain-of-function mutation in resected tumors and/or circulating leukocytes. The posterior fossa, its contents, and the spine were evaluated retrospectively on available MRI and CT images of the head and neck performed for tumor staging and restaging. The transgenic mouse model underwent Microfil vascular perfusion and subsequent intact ex vivo 14T MRI and micro-CT as well as gross dissection, histology, and immunohistochemistry to assess the role of thor(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.Objective Molecular genetic testing for hereditary neuromuscular disorders is increasingly used to identify disease subtypes, determine prevalence, and inform management and prognosis, and although many small disease-specific studies have demonstrated the utility of genetic testing, comprehensive data sets are better positioned to assess the complexity of genetic analysis. Methods Using high depth-of-coverage next-generation sequencing (NGS) with simultaneous detection of sequence variants and copy number variants (CNVs), we tested 25,356 unrelated individuals for subsets of 266 genes. Results A definitive molecular diagnosis was obtained in 20% of this cohort, with yields ranging from 4% among individuals with congenital myasthenic syndrome to 33% among those with a muscular dystrophy. CNVs accounted for as much as 39% of all clinically significant variants, with 10% of them occurring as rare, private pathogenic variants. Multigene testing successfully addressed differential diagnoses in at least 6% of individuals with positive results. Even for classic disorders like Duchenne muscular dystrophy, at least 49% of clinically significant results were identified through gene panels intended for differential diagnoses rather than through single-gene analysis. Variants of uncertain significance (VUS) were observed in 53% of individuals. Only 0.7% of these variants were later reclassified as clinically significant, most commonly in RYR1, GDAP1, SPAST, and MFN2, providing insight into the types of evidence that support VUS resolution and informing expectations of reclassification rates. Conclusions These data provide guidance for clinicians using genetic testing to diagnose neuromuscular disorders and represent one of the largest studies demonstrating the utility of NGS-based testing for these disorders. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.Objective We present here a case report of a patient with a family history of intracerebral hemorrhages (ICHs) who presented with multiple large lobar hemorrhages in rapid succession, with cognitive sparing, who was found to have a mutation in the β-amyloid coding sequence of amyloid precursor protein (Leu705Val), termed the Piedmont-type mutation, the second ever reported case of this form of hereditary cerebral amyloid angiopathy (CAA). Methods Targeted pathologic examination was performed aided by the use of ex vivo MRI. Results Severe CAA was observed mainly involving the leptomeningeal vessels and, to a far lesser extent, cortical vessels, with no amyloid plaques or neurofibrillary tangles. Conclusions This leptomeningeal pattern of β-amyloid deposition coupled with multiple large hemorrhages demonstrates unique pathophysiologic characteristics of CAA associated with the Piedmont-type mutation, suggesting a potential association between leptomeningeal CAA and larger ICHs. Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.Objective To evaluate the diagnostic yield of an 89-gene panel in a large cohort of patients with suspected muscle disorders and to compare the diagnostic yield of gene panel and exome sequencing approaches. Methods We tested 1,236 patients from outpatient clinics across Canada using a gene panel and performed exome sequencing for 46 other patients with sequential analysis of 89 genes followed by all mendelian genes. Sequencing and analysis were performed in patients with muscle weakness or symptoms suggestive of a muscle disorder and showing at least 1 supporting clinical laboratory. Results We identified a molecular diagnosis in 187 (15.1%) of the 1,236 patients tested with the 89-gene panel. Diagnoses were distributed across 40 different genes, but 6 (DMD, RYR1, CAPN3, PYGM, DYSF, and FKRP) explained about half of all cases. Cardiac anomalies, positive family history, age 1,000 IU/L were all associated with increased diagnostic yield. Exome sequencing identified a diagnosis in 10 (21.7%) of the 46 patients tested.
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